Podcast: Play in new window

Subscribe: RSS

Reference:  Denninghoff KR et al. Azithromycin for Preschoolers with Wheezing in the Emergency Department. New England Journal of Medicine. May 2026

Date: July 14, 2026

Dr. Zara Ibrahim

Guest Skeptic: Dr. Zara Ibrahim is a pediatric emergency medicine fellow at Children’s National Hospital in Washington DC where she also completed medical school, pediatric residency. Her research interests include AI applications in medicine and health equity. In her time off, Zara likes to read books, travel, go on long walks to explore DC’s excellent bakery scene, and do HIIT workouts to balance out the pastries.

Case: A 3-year-old with a history of recurrent wheezing presents to the pediatric emergency department (ED) with cough, rhinorrhea, increased work of breathing, and expiratory wheeze. His Pediatric Respiratory Assessment Measure (PRAM) score is 6. He receives albuterol, ipratropium, and dexamethasone with some improvement. His parents ask: “Last time he was sick, someone gave him antibiotics, I think it was ‘Zith something. Would antibiotics help him get better faster?”

Background: Preschool wheeze is best viewed as a heterogeneous clinical syndrome rather than a single diagnosis. Some of these children wheeze mainly during viral illnesses, some may be manifesting an early asthma phenotype, and a smaller number have alternative causes such as bronchiolitis, foreign-body aspiration, anatomic airway abnormalities, etc. Wheezing and asthma exacerbations are frequent reasons for ED care and hospitalization in children. In U.S. data from 2012 to 2020, asthma hospitalization rates were consistently highest among children aged 0 to 4 years and decreased across successive pediatric age groups.

During an acute asthma-like episode, airway inflammation, mucosal edema, mucus hypersecretion, and bronchial smooth-muscle constriction further narrow the airways.  This can produce expiratory wheeze, prolonged expiration, tachypnea, retractions, reduced air entry, and, in more severe episodes, hypoxemia. Viral respiratory infections are the most common triggers of acute wheezing and asthma exacerbations in young children, with rhinovirus and respiratory syncytial virus among the frequently identified pathogens. Because preschool children can’t typically perform reproducible spirometry, emergency clinicians rely on clinical examination, pulse oximetry, and validated bedside severity scores such as the Pediatric Respiratory Assessment Measure, or PRAM. The PRAM is a bedside score from 0 to 12 based on oxygen saturation, suprasternal retractions, scalene-muscle contraction, air entry, and wheezing; higher scores indicate greater severity.

The immediate ED goal is to rapidly assess exacerbation severity, identify impending respiratory failure, and reassess the child’s response to treatment, rather than assign a permanent diagnostic label during a single acute visit. Standard management includes inhaled short-acting beta₂-agonists, early systemic glucocorticoids for moderate-to-severe exacerbations when appropriate, supplemental oxygen for hypoxemia, and repeated clinical assessment. Antibiotics are not routinely recommended for an asthma-like exacerbation unless there is a separate bacterial indication.

Two biologically plausible arguments have been advanced in support of azithromycin.

First, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are often detected in the upper airways of young children, and observational studies have associated colonization or microbiome profiles dominated by these organisms with more severe lower respiratory illness and later recurrent wheeze or asthma. These associations raised the hypothesis that bacteria may contribute to some episodes, but nasopharyngeal detection can represent colonization and, by itself, does not establish lower-airway bacterial infection or causation.

Second, macrolides have immunomodulatory and anti-inflammatory actions distinct from their antibacterial activity. Earlier outpatient randomized trials in selected children suggested that azithromycin, particularly when started very early in a respiratory illness before substantial airway obstruction developed, might shorten episodes or reduce progression to severe lower respiratory illness. In contrast, an earlier ED-based placebo-controlled trial found no reduction in symptom duration, short-acting beta₂-agonist use, or time to the next exacerbation. These mixed findings raised an important timing-and-severity question: might azithromycin have a pre-emptive effect early in an illness but little or no effect once moderate-to-severe wheezing is established?

Clinical Question: In preschool children presenting to the ED with moderate-to-severe wheezing, does a 5-day course of azithromycin reduce wheezing-related symptom severity compared with placebo?

  • Population: Children 18 to 59 months old presenting to one of eight PECARN-affiliated pediatric EDs with moderate-to-severe expiratory wheezing, defined as PRAM score ≥4
    • Excluded: Children with antibiotics in the prior two weeks, acute infection requiring systemic antibiotics, recent systemic glucocorticoids for wheezing, suspected foreign-body aspiration, prematurity, systemic illness other than allergies, azithromycin allergy, or active COVID-19.
  • Intervention: Azithromycin 12 mg/kg orally once daily for 5 days.
  • Comparison: Matching placebo for 5 days
  • Outcome:
    • Primary Outcome: Sum of Asthma Flare-up Diary for Young Children scores over 5 days. Scores ranged from 5 to 35, with higher scores indicating worse symptoms.
    • Secondary Outcomes: ED length of stay, hospital length of stay, return ED visits or hospitalization within 72 hours, bacterial clearance, antimicrobial resistance, and adverse events.
  • Type of Study: A multicentre, parallel-group, masked, placebo-controlled superiority randomized controlled trial.

Authors’ Conclusions: “Azithromycin did not lead to a greater reduction in the severity of wheezing-related symptoms than placebo in preschool-age children who presented to the emergency department with moderate-to-severe acute wheezing.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized? Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Unsure
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes 
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No
  12. Financial conflicts of interest. The study was funded by NHLBI/NIH and PECARN, and the funders reportedly had no role in design, analysis, interpretation, manuscript writing, or publication decisions.

Results: A total of 840 children were randomized. Of these, 521 (62%) tested positive for at least one of the three pathogenic bacteria, and 312 tested negative. Around half of the patients were hospitalized. The trial was stopped early for futility after an interim analysis

Key Results: Adding five days of azithromycin to standard ED treatment did not reduce wheezing-related symptom severity compared with placebo.

Primary Outcome: ADYC Symptoms Score

There was no significant improvement in wheezing-related symptom severity with azithromycin, whether children had the prespecified bacteria detected or not.

Secondary Outcomes: No meaningful differences were seen in ED length of stay, hospital length of stay, or 72-hour return ED visits/hospitalizations.

  • Bacterial Clearance: Among bacteria-positive children with follow-up testing, azithromycin cleared the prespecified bacteria more often than placebo: 58.7% vs 11.4%.
  • Adverse Events and Resistance: Adverse events were similar between groups, and no deaths occurred. Antimicrobial resistance at follow-up was similar among those who returned for follow-up testing, but the bacterial follow-up sample was incomplete

Negative Study:

This was a negative study. This is important because we know there is publication bias, where studies with positive or exciting findings are more likely to be submitted, accepted, published, promoted, and remembered. Negative trials can quietly disappear, leaving clinicians with an inflated sense that an intervention works.

A well-done negative trial can be just as valuable as a positive one because it helps us stop doing things that do not help patients.

Selection Bias/Generalizability: 

The flow diagram in Figure 1 provides food for thought. More than 2,600 children were eligible, but only 840 underwent randomization. Among families approached, about 64% declined to consent. In addition, some eligible families were never approached because of staffing, guardian availability, language, or administrative issues. This also included a small group where the provider had a clinical preference.

This introduces selection bias.

The children enrolled in the trial may not perfectly represent all preschoolers with wheezing who show up to the ED. For example, we do not know whether families who declined had strong feelings about antibiotics. Did some parents want azithromycin and not want to risk placebo? Did some parents want to avoid antibiotics and not want to risk receiving azithromycin? Were some families too stressed, too busy, or too overwhelmed to consider research participation? We do not know.

The same question applies to clinicians. If a provider had a strong clinical preference, what was that preference? Did they really want to give antibiotics? Did they really want to avoid them? The paper does not tell us.

This does not undermine the internal treatment comparison among randomized children, but it may produce a trial population whose families, health literacy, treatment preferences, illness timing, or ability to complete electronic diaries differ from those seen in routine practice. The eight sites were also specialist pediatric EDs within a research network, so generalizability to community EDs, rural settings, or health systems outside the United States is less certain.

Stopping Early: 

We have talked before on the SGEM about the risks of stopping trials early. When trials are stopped early for apparent benefit, they can overestimate treatment effects. This can also create problems for systematic reviews and meta-analyses, because early-stopped trials may contribute exaggerated effect sizes and make pooled estimates harder to interpret.

In this study, the concern is a little different. The data and safety monitoring board stopped the trial after a planned interim analysis with a prespecified futility showing conditional power below 16% in both cohorts. This stoppage feels more reasonable from an ethical and practical standpoint: why keep enrolling children if the chance of showing meaningful benefit is very small?

But stopping early still comes with a trade-off. The authors appropriately acknowledge that early stopping reduced the sample size, decreased precision, and reduced statistical power. So, while this trial the near-zero point estimates make a moderate or large benefit benefit of azithromycin unlikely, it is less able to exclude very small effects, return visits, adverse events, resistance, and treatment-by-subgroup interactions. The question becomes: even if there were a tiny benefit, would it be clinically meaningful enough to justify antibiotics, side effects, and antimicrobial stewardship concerns? Probably not.

POOs vs LOOs:

In this trial, the thing we care about most is whether the child feels better, breathes better, leaves the ED or hospital sooner, or avoids coming back. Those are patient-oriented outcomes.

The detection of respiratory pathogens from a nasopharyngeal swab is different. That is a lab-oriented outcome. It does not automatically tell us whether the pathogen is causing the child’s current symptoms or whether treating it will improve outcomes. That distinction really matters here. Many children had bacteria or viruses detected, and azithromycin did increase bacterial clearance. But that lab signal did not translate into clinical benefit. Children did not have symptom scores that were meaningfully better, shorter ED or hospital stays, or fewer return visits.

A side point is that PCR testing is very sensitive. It can detect genetic material from organisms, but it cannot always tell us whether that organism is alive, actively causing disease, simply hanging out in the airway, or left over from a recent infection. Prior community surveillance studies have shown that many children can test positive for respiratory viruses even when asymptomatic, and detection can persist.

Do not confuse detecting a pathogen with proving it is the problem. Lab results can be interesting, but patients do not care if we clear a swab. They care about breathing easier, going home sooner, and avoiding harm from unnecessary antibiotics.

Do We Really Use That Many Antibiotics?

The authors mention that up to one-fourth of preschool wheezing episodes are treated with antibiotics. That number made us pause.

This is not saying that one-fourth of children with wheeze receive azithromycin specifically. It refers to antibiotics more broadly. It does raise an important antibiotic stewardship issue. Preschool wheeze is commonly associated with viral infections and airway inflammation, not bacterial disease requiring antibiotics.

The stewardship message is for preschool children with wheezing, treat the wheeze. Do not routinely treat the swab.

Comment on the Authors’ Conclusion Compared to the SGEM Conclusion:  We agree with the authors’ conclusion.

SGEM Bottom Line: Azithromycin should not be routinely prescribed for preschool children presenting to the ED with moderate-to-severe wheezing unless there is another clear indication for antibiotics.

Case Resolution: The 3-year-old receives bronchodilator therapy and dexamethasone. He improves clinically, maintains oxygen saturation, and has no focal lung findings or other signs of bacterial infection. You discuss the evidence with the family and do not prescribe azithromycin. He is discharged with a recommendation to follow up with his primary care clinician.

Clinical Application: This trial supports antibiotic stewardship. Preschool wheeze is often viral or inflammatory, and even when nasopharyngeal bacteria are detected, azithromycin did not have any statistical or clinically significant benefits. Antibiotics should be reserved for children with clinical evidence of bacterial infection, not used reflexively for wheezing alone.

What Do I Tell the Patient? Most wheezing episodes in preschool children are triggered by viruses or airway inflammation. We do not have evidence that azithromycin can help children breathe better, faster, shorten their visits, or prevent return visits. Antibiotics can also cause side effects as well. Let’s focus on treatments for wheezing, such as steroids and albuterol.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References

Trottier ED, Chan K, Allain D, Chauvin-Kimoff L; Canadian Paediatric Society, Acute Care Committee and Paediatric Emergency Medicine Section. Managing an acute asthma exacerbation in children. Paediatr Child Health.2021;26(7):438.

Binney S, Flanders WD, Sircar K, Idubor O. Trends in US pediatric asthma hospitalizations, by race and ethnicity, 2012–2020. Prev Chronic Dis. 2024;21:E71. doi:10.5888/pcd21.240049.

Heymann PW, Carper HT, Murphy DD, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol. 2004;114(2):239–247.

National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute; 2007

Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487–1495. doi:10.1056/NEJMoa052632.

Teo SM, Mok D, Pham K, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015;17(5):704–715. doi:10.1016/j.chom.2015.03.008.

Zhu Z, Camargo CA Jr, Raita Y, et al. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: a multicenter prospective study. J Allergy Clin Immunol. 2022;150(4):806–816.

Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615. doi:10.1128/CMR.00078-09

Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1–3 years: a randomized, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):19–26. doi:10.1016/S2213-2600(15)00500-7.

Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA.2015;314(19):2034–2044. doi:10.1001/jama.2015.13896.

Mandhane PJ, Paredes Zambrano de Silbernagel P, Aung YN, et al. Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: a placebo-controlled randomized trial. PLoS One.2017;12(8):e0182411. doi:10.1371/journal.pone.0182411.

Guyatt, GH, Briel, M, Glasziou, P, et al. Problems of stopping trials early. BMJ 2012; 344.